Dual Immunotherapy Combination Demonstrates Superior Survival Outcomes in Advanced Lung Cancer: Key Findings from ARC-10 Trial

Breakthrough Results Challenge Current Treatment Standards

A landmark clinical trial has revealed compelling evidence that combining two immunotherapeutic agents—domvanalimab and zimberelimab—significantly outperforms single-agent therapy in treating advanced non-small cell lung cancer (NSCLC) patients with high PD-L1 expression. The study, part of the ARC-10 program, provides the first published survival advantage data for this dual checkpoint inhibitor approach in front-line treatment settings.

Survival Advantage: How the New Combination Performs

The most striking finding involves overall survival metrics. Patients receiving the domvanalimab plus zimberelimab regimen experienced a median overall survival that has not yet been reached at the time of analysis, contrasting sharply with the zimberelimab-alone group, which achieved 24.4 months median survival. This translates to a 36% reduction in mortality risk (hazard ratio of 0.64) when comparing the combination therapy to single-agent zimberelimab.

Among patients treated with chemotherapy alone, median overall survival reached only 11.9 months—highlighting how profoundly immunotherapy approaches have reshaped treatment outcomes. At the 12-month mark, survival rates tell a similar story: 68% of combination-treated patients remained alive compared to 57% in the zimberelimab-only cohort and 50% receiving chemotherapy.

Progression-Free Survival and Response Rates Paint a Consistent Picture

Beyond overall survival, the progression-free survival data reinforce the superiority of dual inhibition. Patients on the combination therapy achieved a median progression-free survival of 11.5 months versus 6.2 months for zimberelimab monotherapy—an 85% improvement. The chemotherapy control arm showed 9.6 months median progression-free survival, underscoring how immunotherapy fundamentally alters disease trajectory.

Objective response rates—the proportion of patients experiencing measurable tumor shrinkage—further support this trend. The domvanalimab-zimberelimab combination induced confirmed responses in 44.7% of evaluable patients, compared to 35.0% for zimberelimab alone and 35.3% for chemotherapy. While the numerical difference appears modest, the durability and tolerability advantages prove equally important.

Safety Profile: Why Tolerability Matters as Much as Efficacy

A critical advantage of immunotherapy combinations lies in their safety profile relative to traditional chemotherapy. Treatment-related adverse events requiring therapy discontinuation occurred in just 10.5% of patients receiving the dual immunotherapy combination, compared to a substantially higher rate of 23.5% for platinum-based chemotherapy. Single-agent zimberelimab showed the lowest discontinuation rate at 7.5%, suggesting that domvanalimab adds modest tolerability burden, though far below chemotherapy toxicity levels.

Serious adverse events tell a more nuanced story. Grade 3 or higher treatment-related adverse events affected 21.1% of combination-therapy patients, 15.0% of zimberelimab monotherapy recipients, and 47.1% of chemotherapy recipients. Notably, infusion-related reactions remained infrequent in both immunotherapy groups (7.9% for the combination, 2.5% for zimberelimab alone, and 0% for chemotherapy), suggesting generally favorable tolerability during drug administration.

Death attributable to treatment proved rare across all arms but warrants careful interpretation. The combination therapy resulted in one treatment-related death (2.6%), zimberelimab monotherapy in four deaths (10.0%), and chemotherapy in two deaths (11.8%). These small absolute numbers require cautious interpretation, yet the safety profile still favors immunotherapy over conventional chemotherapy.

Understanding the Mechanism: Why Blocking Two Checkpoints Matters

The scientific rationale underlying this combination strategy involves simultaneous inhibition of two distinct immune checkpoint pathways. Domvanalimab targets TIGIT (T-cell immunoreceptor with Ig and ITIM domains), a relatively newly appreciated checkpoint on immune cells that acts as a brake on anti-tumor immunity. What distinguishes domvanalimab is its Fc-silent design—a structural modification that allows it to block TIGIT signaling while avoiding depletion of regulatory T cells, thereby potentially reducing immune-related toxicity.

Zimberelimab, by contrast, targets PD-1 (programmed cell death protein-1), an established checkpoint whose inhibition has revolutionized cancer treatment over the past decade. By restraining this well-characterized pathway, zimberelimab restores T-cell activation and anti-tumor function.

The hypothesis behind combination therapy suggests these pathways play complementary, non-redundant roles in suppressing immunity. Blocking both simultaneously may produce greater immune activation than targeting either pathway alone—a premise supported by the ARC-10 survival data.

Study Design and Patient Population

The trial enrolled 98 patients across three treatment arms, with 95 receiving at least one dose of study medication. Patients were randomized 2:2:1 to receive either domvanalimab-zimberelimab, zimberelimab monotherapy, or platinum-doublet chemotherapy every three weeks. Enrollment focused exclusively on treatment-naïve patients with locally advanced or metastatic squamous or non-squamous NSCLC featuring PD-L1 tumor proportion scores of 50% or greater and lacking actionable driver mutations (such as EGFR, ALK, or ROS1 alterations) for which targeted therapies exist.

The median follow-up duration reached 24.5 months at data cutoff (May 17, 2024), with 22 patients remaining on active treatment—11 in the combination arm, 10 receiving zimberelimab monotherapy, and one continuing chemotherapy. This extended follow-up duration provides reasonably mature survival data, though some patients continue treatment.

Clinical and Research Implications

These findings represent the first evidence demonstrating overall survival improvement for domvanalimab-zimberelimab in any indication. The results align with growing preclinical and translational evidence suggesting that Fc-silent anti-TIGIT antibodies may offer distinct efficacy and safety characteristics compared to Fc-enabled TIGIT inhibitors previously evaluated in clinical trials.

For the broader oncology community, the data support the emerging paradigm of rational combination immunotherapy—moving beyond single checkpoint inhibition toward synergistic dual targeting of complementary immune evasion mechanisms. The trial continues to evolve, with additional planned comparisons including pembrolizumab, an alternative PD-1 inhibitor, to further contextualize these findings within the contemporary treatment landscape.

The ARC-10 study was conducted through a partnership between Arcus Biosciences and Gilead Sciences, reflecting collaborative efforts to evaluate novel therapeutic combinations for patients with advanced malignancies lacking standard-of-care precision medicine options. These preliminary results will be presented in detail at the Society for Immunotherapy of Cancer Annual Meeting, offering the research and clinical communities comprehensive access to study data, efficacy analyses, and safety assessments that may influence future trial designs and treatment algorithms in PD-L1-high NSCLC.